Sepsis is a leading cause of death in critically ill patients, with up to 750,000 people developing this disease each year in the United States. The intestine plays a central role in the development of sepsis, and is considered to be the "motor" of the systemic inflammatory response. Epidermal growth factor (EGF) is a peptide that has been shown to protect the intestinal epithelium in several injury models. EGF is primarily involved in regulating cell survival, cell replication, and cell movement in various cell types. It is not clear if the protective effects of EGF are specific to the intestine, or if EGF influences other tissues and organ systems that indirectly protect the intestine. The central hypothesis of this proposal is that exogenous administration of EGF will improve survival in sepsis by directly modulating the integrity of the intestinal epithelium. Since the role of EGF in sepsis is unknown, the first aim of this investigation is to determine how EGF and its receptor, EGF-R, modulate intestinal integrity in mice subjected to two models of sepsis: cecal ligation and puncture and pneumonia. Intestinal epithelial apoptosis will be evaluated following manipulation of the EGF/EGF-R axis by a) systemic administration of EGF, b) using transgenic mice that over express EGF in their intestines and c) using mice with defective EGF-R signaling capacity. The functional significance of the epithelial alterations will be examined by determining if systemic EGF improves survival and if the intestine specific effects of EGF are sufficient to improve mortality. The second aim will then examine the mechanisms by which EGF prevents sepsis-induced intestinal epithelial apoptosis. By targeting signaling molecules in an intestine-specific fashion, we will mechanistically evaluate whether the anti-apoptotic effects of EGF are 1) mediated via PI3K/Akt signaling and 2) dependent on NFkB activation. These studies will help determine the functional significance of systemic administration of EGF in sepsis and the mechanisms underlying its effects. This has large public health implications as it could potentially be used as a novel therapeutic in the treatment of a disease that kills 210,000 patients a year.